Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional)

The National Institutes of Health (NIH) is reissuing its notice of funding opportunity (NOFO) for the development of precision probiotic interventions under activity code R61/R33 (Exploratory/Developmental Phased Award). This NOFO is a joint initiative from NIH divisions such as the National Center for Complementary and Integrative Health (NCCIH), National Institute on Aging (NIA), National Institute of Dental and Craniofacial Research (NIDCR), and National Cancer Institute (NCI), with potential co-funding from the Office of Research on Women's Health (ORWH). Its primary aim is to support innovative mechanistic research that addresses the inconsistencies often found in probiotic therapy responses due to human biological variability. This two-phase funding mechanism encourages studies that will assess host biological patterns impacting probiotic responses and establish causality in modifying probiotic efficacy through rigorous preclinical or clinical mechanistic studies. The funding is structured in two distinct phases: the R61 phase (up to two years) is for observational and secondary data analysis to identify biological patterns like microbiome composition, immune markers, genetic factors, and lifestyle factors that correlate with probiotic effects. The R33 phase (remaining years, totaling a five-year limit for both phases) focuses on validating these patterns’ causal impact on probiotic responses through mechanistic studies, potentially using animal models or human subjects. Notably, clinical efficacy trials are outside the scope of this NOFO, as the research should focus on understanding how probiotic interventions work rather than proving effectiveness. A total budget of $350,000 in direct costs per year is available across both phases, with funding awarded based on NIH appropriations and the quality of submitted applications. Importantly, transition from the R61 to the R33 phase is conditional, requiring NIH administrative review and approval. Applicants must achieve predefined milestones in the R61 phase, such as identifying specific host biological markers and demonstrating statistical significance and relevance in predictive models, to progress to the R33 phase. Eligible applicants include higher education institutions, nonprofits, small businesses, local and state governments, tribal organizations, and certain federal government entities. While foreign organizations cannot apply, U.S. organizations with foreign components may be eligible. Registration with multiple federal systems, including SAM, eRA Commons, and Grants.gov, is required before application submission. Applications must also contain a Plan for Enhancing Diverse Perspectives (PEDP), focusing on inclusive research approaches, and failure to submit this plan will lead to administrative withdrawal of the application. Applications are reviewed by the NIH Center for Scientific Review (CSR) with evaluations based on significance, innovation, and feasibility. Criteria emphasize the importance of addressing biological patterns that could explain variances in probiotic outcomes, the rigor of research methods, and the potential for diverse perspectives to enhance scientific outcomes. Reviewers will also assess the PEDP’s alignment with the study's objectives and the applicant's strategies for inclusive research practices. The application deadline for the first cycle is June 2, 2025, with subsequent cycles occurring biannually until June 2, 2027. Interested applicants should consult the scientific and financial contacts provided by NIH to clarify specific eligibility or submission questions. The research must adhere to NIH policies, and investigators planning FDA-regulated studies on probiotics should confirm IND requirements. Awardees are expected to submit annual performance reports and a final progress report, as per NIH reporting standards.